Increased Expression of β-Amyloid Precursor Protein During Neuronal Differentiation is Not Accompanied by Secretory Cleavage

Despite increasing evidence for a pathogenetic role for the β-amyloid precursor protein (βAPP) in Alzheimer disease, the physiological function of the protein remains unclear. The expression of the neural-specific isoform containing 695 amino acids, βAPP695, is consistent with a role for the protein in neuronal development. In this study, we analyzed the expression of βAPP during the retinoic acid-induced neuronal differentiation of P19 murine embryonal carcinoma cells. Northern blot and RNase protection analyses show a selective increase in βAPP695 expression, concomitant with the morphologic differentiation of P19-derived neurons. Moreover, the time course of increase observed for the βAPP695 mRNA is paralleled by other neuronal-specific transcripts. A similar increase in βAPP695 is observed at the protein level. Furthermore, we show that levels of βAPP695 protein progressively increase during the in vitro differentiation of primary hippocampal neurons. The finding that β APP695 increases selectively and progressively during neuronal differentiation in two different cell culture systems suggests that this isoform has an important cellular function during this process in the brain. Unlike βAPP in most peripheral cell types, the increased levels of βAPP found in terminally differentiated neuronal cells are not processed in significant amounts by secretory cleavage. Thus, differentiation of neurons is accompanied by increased βAPP695 expression and membrane retention of the protein as intact, full-length molecules that could serve as potential substrates for amyloidogenesis.